Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early-Onset Obesity

Abstract

Pseudohypoparathyroidism type 1A (PHP1A), pseudoPHP (PPHP), and PHP type 1B (PHP1B) are caused by maternal and paternal GNAS mutations and abnormal methylation at maternal GNAS promoter(s), respectively. Adult PHP1A patients are reportedly obese and short, whereas most PPHP patients are born small. In addition to parathyroid hormone (PTH) resistance, PHP1A and PHP1B patients may display early-onset obesity. Because early-onset and severe obesity and short stature are daily burdens for PHP1A patients, we aimed at improving knowledge on the contribution of the GNAS transcripts to fetal and postnatal growth and fat storage. Through an international collaboration, we collected growth and weight data from birth until adulthood for 306 PHP1A/PPHP and 220 PHP1B patients. PHP1A/PPHP patients were smaller at birth than healthy controls, especially PPHP (length Z-score: PHP1A -1.1 ± 1.8; PPHP -3.0 ± 1.5). Short stature is observed in 64% and 59% of adult PHP1A and PPHP patients. PHP1B patients displayed early postnatal overgrowth (height Z-score at 1 year: 2.2 ± 1.3 and 1.3 ± 1.5 in autosomal dominant and sporadic PHP1B) followed by a gradual decrease in growth velocity resulting in normal adult height (Z-score for both: -0.4 ± 1.1). Early-onset obesity characterizes GNAS alterations and is associated with significant overweight and obesity in adults (bodey mass index [BMI] Z-score: 1.4 ± 2.6, 2.1 ± 2.0, and 1.4 ± 1.9 in PPHP, PHP1A, and PHP1B, respectively), indicating that reduced Gsα expression is a contributing factor. The growth impairment in PHP1A/PPHP may be due to Gsα haploinsufficiency in the growth plates; the paternal XLαs transcript likely contributes to prenatal growth; for all disease variants, a reduced pubertal growth spurt may be due to accelerated growth plate closure. Consequently, early diagnosis and close follow-up is needed in patients with GNAS defects to screen and intervene in case of early-onset obesity and decreased growth velocity. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

Keywords: EARLY-ONSET OBESITY; GNAS; GROWTH; PSEUDOHYPOPARATHYROIDISM; PSEUDOPSEUDOHYPOPARATHYROIDISM.

Figure 1

Schematic drawing of the GNAS locus The imprinted human GNAS locus (not to scale, Hg19-chr20:57,414,795–57,486,250) and the STX16 gene (Hg19-chr20:57,226,309–57,254,5812) on chromosome 20. The centromeric/telomeric (cen/tel) orientation of the chromosome is indicated. Boxes indicate coding exons. Black boxes: transcripts expressed from both parental allele; grey boxes: transcripts expressed only from the paternal allele; white box: transcript expressed predominantly from the maternal allele. Stars indicate the differentially methylated regions. Arrows: transcription (direction and parental origin). Transcripts are drawn above (mat: maternal) or below (pat: paternal) the GNAS locus and the STX16 gene; for clarity, the N1 exon that is located between exon 3 and 4 of GNAS, and is alternatively spliced, has not been included in this scheme. Sense transcripts (NESP, XLαs, A/B and Gsα) have their own first exon and share GNAS exons 2 to 13.

Figure 2

Longitudinal evolution of length/height depicted for the different disorders. Boys and girls affected with inactivating PTH/PTHrP Signaling Disorder or iPPSD2 [PHP1A (red dots and lines) or PPHP (blue dots and lines)] or iPPSD3 [AD-PHP1B (green dots and lines) or spor-PHP1B (black dots and lines)] are plotted on the WHO growth charts. Panels A, B, C and D zoom in the first years of life. Panels E, F, G and H depict the pattern of growth from birth to 18 years (adult height). Note the moderate acceleration of growth in the first years of life in iPPSD2 while with growth velocity is dramatically increased from birth in iPPSD3.

Figure 3

Z-scores of adult height and BMI of patients affected with the different GNAS genetic and epigenetic lesions. Raw data (dots), means and SD (lines) are presented. A and B: comparison of the final heights and BMI z-scores between the different diseases. Statistically different means (p<0.05) are indicated by *, (p<0.001) are indicated by **, (p<0.0001) are indicated by ***. Note that the scale differs between the panels. C and D represent the data divided according to the sex; E and F represent the data divided according to the genotype of the PHP1A patients.

Figure 4

Longitudinal evolution of BMI (kg/m²) depicted for the different disorders. Boys and girls affected with iPPSD2 [PHP1A (red dots and lines) or PPHP (blue dots and lines)] or iPPSD3 [AD-PHP1B (green dots and lines) or spor-PHP1B (black dots and lines)] are plotted on the BMI WHO charts. Panels A, B, C and D show the first three years of life. Panels E, F, G and H depict the pattern of growth from birth to 18 years (adulthood). Note the dramatic increase in weight gain occurring very early in life in the four diseases variants.